Legacy in Cardiovascular Risk Factors Control: From Theory to Future Therapeutic Strategies?
Abstract
:1. Introduction
2. Diabetes
2.1. Legacy Effect in Diabetic Patients
2.2. “Metabolic Memory”: What Is Hidden behind the Legacy Effect
3. Hypercholesterolemia
3.1. Legacy Effect from Optimization of Lipid Profile
3.2. Trained Immunity: oxLDL “Memory”
4. Hypertension
4.1. Legacy Effect of Optimized Blood Pressure Control
4.2. Ang II “Memory”
5. Discussion
6. Perspectives
7. Conclusions
Author Contributions
Funding
Conflicts of Interest
References
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Study Name Type | Patients Characteristics (n int/n Follow-Up) | Effect of Intervention (Study Duration) | Legacy Effect (Follow-Up Duration) | Comments | |
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Diabetes | DCCT RCT EDIC OFU | T1DM Mean age 27 y (1441/1394) | (6.5 y) (−) 53% severe retinopathy (−) 40% clinical neuropathy (−) 61 % microalbuminuria | (17 y) Legacy effect of intervention (−) 57% nonfatal MI, stroke, or death from CVD (−) 46% nephropathy | In OFU Hb1Ac 7.9% intensive vs. 7.8% conventional |
UKPDS RCT/OFU | Newly diagnosed T2DM Mean age 56.4 y (3867/3277) | (10 y) (−) 12% diabetes-related endpoints (−) 10% diabetes-related death (−) 25% microvascular endpoints | (10 y) Legacy effect of intervention (−) 9% diabetes-related endpoints (−) 24% microvascular endpoints (−) 15% MI (−) 13% death from any cause | No difference in Hb1Ac in OFU | |
VADT RC/OFU | T2DM long-duration (11.5 y) poorly controlled Mean age 60.4y (1791/1391) | (5.6 y) No difference in major CV outcomes, death, or microvascular complications except for progression of albuminuria (13.1% vs. 9.1% in int. treat. group) | (10 y) Legacy effect of intervention (−) 17% major CV events (15 y) No difference in major CV events or death | 40% already had CV event at inclusion HbA1c curves still separated at 10 y follow-up, no more at 15 y | |
ACCORD RCT ACCORDION OFU | T2DM long-duration (10 y) Mean age 62.2 y (10,251/8601) | (3.5 y) No effect on primary composite endpoint (non-fatal MI, non-fatal stroke, or death) (−) 24% MI in int. treat. group (+) 22% death from any cause (+) 36% death from CV causes in int. treat group | (9 y) No effect on primary composite endpoint Trend to lower non-fatal MI (+) 20% death from CV causes in int. group | 35% had previous CV event | |
ADVANCE RCT ADVANCE-ON OFU | T2DM long-duration (8 y) ≥55 y ≥1 CV risk factor or history of major macro- or microvascular disease (11,140/8494) | (5 y) (−) 10% combined major micro- and macrovascular events (−) 21% nephropathy No effect on major macrovascular events, CV death, or death from any cause | (6 y) No differences in risk of death or major CV events (−) 46% end stage renal disease but very few events | ||
ADDITION Registered based non-RCT | Newly diagnosed T2DM after screening compared to unscreened population Mean age 59.9 y (registered 153,107, diagnosed 1533) | (5 y screening period) No comparison in intervention Diabetes detected 2.2 y earlier in screened group | (10 y) In screened group: HR 0.79 lower mortality HR 0.80 lower CV mortality HR 0.66 lower diabetes-related mortality HR 0.84 lower CVD event | No effect at national population level | |
DAS Cohort study | Newly diagnosed T2DM Mean age 56.8 y Stratified by mean Hb1Ac during first year, comparison to Hb1Ac < 6.5% (34,737) | NA | (10 y) - Hb1Ac ≥ 6.5% within first year: increased micro- and macro-CV events (HR 1.2) - Hb1Ac ≥ 7.0% within first year, increased mortality (HR 1.29) - ≥8.0% for more than 2 y increased microvascular event and mortality risk | ||
Lipid profile | LIPID RCT LIPID FU OFU | Pravastatin vs. placebo in recent MI or unstable angina Median age 62 y Median cholesterol 218 mg/dl (9014/7680) | (6 y) Vs. placebo: (−) 24% RR death from CHD (−) 22% RR overall mortality (−) 29% RR MI (−)19% RR stroke | (2 y) Open-label period, crossover 86% gr. placebo on pravastatin 88% gr. prava still on pravastatin, with similar cholesterol level Legacy effect of intervention (−) 25% RR death from CHD (−) 19% RR overall mortality (−)15% RR MI (−) 24% RR stroke | |
ASCOT-LLA RCT UK ASCOT-LLA legacy OFU | Atorvastatin vs. placebo in hypertensive patients with at least 3 other CV risk factors in primary prevention Mean age 61.4 y (4605/4432) | (3.3 y) Favor atorvastatin HR 0.64 for non-fatal MI and fatal CHD HR 0.79 for CV events HR 0.71 for coronary events Trend to less death (HR 0.87, p = 0.16) | (11 y) Open-label crossover (2/3 placebo on statin) Legacy effect favored atorvastatin HR 0.86 all-cause mortality HR 0.85 non-CV death HR 0.89 CV death but not significant | ||
WOSCOPS RCT WOSCOPS FU OFU | Pravastatin vs. placebo in primary prevention in men Mean age 55 y High LDL (6596/6408) | (4.9 y) Favor pravastatin: (−) 31% RR in non-fatal MI or death from CHD (−) 32% RR in death from CV causes | (18 y) 38.7% (former prava) and 35.2% (former placebo) at 5 y on statin, no further data Legacy effect favored pravastatin: (−) 13% mortality (−) 21% RR in death from CV causes | ||
ACCORD-LLA RCT ACCORDION OFU | Combined therapy (simvastatin + fibrate vs. simva+ placebo) in T2D long-duration with dyslipidemia Mean age 61.8 y (940/765) | (5 y) No effect of combined treatment on CV outcomes or mortality | (10 y) Same level of lipid profile in both groups but legacy effect of combined treatment HR 0.68 in all-cause mortality HR 0.63 in CVD mortality HR 0.66 in major CHD | ||
HOPE-3 RCT HOPE-3 FU OFU | Rosuvastatin vs. placebo, at least 1 CV risk factor, no CV disease Mean age 65.7 y (12,705/9326) | (5.6) Favor rosuvastatin HR 0.76 in MACE-1 (composite of death from CV causes, non-fatal MI, non-fatal stroke) HR 0.75 in MACE2 (composite of revascularization, HF, resuscitated CA) | (3.1) Legacy effect of rosuvastatin treatment HR 0.80 MACE-1 HR 0.83 MACE -2 Total FU: HR 0.79 MACE-1 HR 0.79 MACE -2 | In OFU: 37% on statin (36% of former rosu, 38% of former placebo group) | |
ALLHAT-LLT RCT ALLHAT-LLT OFU | Pravastatin vs. usual care in hypertensive patient + at least 1 CV risk factor Mean age 66 y (10,355/1672) | (4.8 y) No effect on all-cause mortality or CHD | (8–13 y) No legacy effect | Only 16% difference in LDL between groups at end of intervention period | |
Blood pressure | SHEP RCT SHEP FU OFU | Chlortalidone +/− atenolol vs. placebo in isolated hypertensive patients Mean age 71.6 y (4736/1885) | (4.5 y) Favor intervention 0.64 RR in stroke 0.73 RR in non-fatal MI + 0.46 RR LV failure | (22 y) Legacy effect of intervention HR 0.89 CV death One day of life expectancy gained in intervention group per month of treatment | |
ROADMAP RCT ROADMAP OFU OFU | Olmesartan vs. placebo in T2D patients ≥ 1 CV risk factor Mean age 57.7 y (4447/1758) | (3.2 y) Increased time to onset of microalbuminuria (25%) | (6 y) Despite crossover and increase in BP, legacy effect of olmesartan OR 0.34 in diabetic retinopathy OR 0.23 in CHF | ! higher rate of fatal CV events in int. group in patients with pre-existing CHD | |
ASCOT RCT ASCOT legacy OFU | Amlodipine (+/− perindopril) vs. atenolol (+/− thiazide) hypertensive patients ≥ 3 other CV risk factors Mean age 63 y (19,257/8580) | (5.5 y) Favor amlodipine-based regiment HR 0.77 stroke (fatal and non-fatal) HR 0.84 in CV events HR 0.76 in CV mortality HR 0.70 in new onset of diabetes | (16 y) Legacy effect of amlodipine-based regiment HR 0.71 death from stroke | ||
UKPDS 38 RCT FU OFU | Tight vs. less-tight blood pressure control T2DM patients (captopril and atenolol) Mean age 56.8 y (1148/884 ) | (8.4 y) Favor tight control (−) 24% diabetes-related endpoints (−) 32% diabetes-related deaths (−) 44% strokes (−) 37% microvascular endpoints | (10 y) Legacy effect favored tight control 0.50 RR in peripheral vascular disease | ||
HOPE-3 RCT HOPE-3 FU OFU | Candesartan + HCTZ vs. placebo at least 1 CV risk factor No CV disease Mean age 65.7 y (12,705/9326) | (5.6 y) No significative difference, except in subgroup > 143.5 mmHg HR 0.73 MACE 1 HR 0.76 MACE 2 | (3.1 y) Legacy effect in subgroup > 143.5 mmHg HR 0.76 MACE 1 | 2/3 in follow-up 1 ≥ BP-lowering drug and 30% on 2 ≥ BP-lowering drugs (similar in both groups) | |
ALLHAT RCT | Hypertensive patients+ ≥1 CHD risk factor, chlortalidone vs. amlodipine vs. lisinopril Mean age 67 y (32,804/27,755) | (4.9 y) No difference Increase in HF for amlodipine Increase in stroke mortality for lisinopril | (8–13 y) No legacy effect | ||
ANBP2 RCT ANBP2 FU OFU | Hypertensive patients ACE inhibitor vs. diuretics Mean age 72 y (6083/5378) | (4.1 y) Favor ACE inhibition HR 0.89 CV event or death HR 0.68 nonfatal MI but HR 1.91 for fatal stroke | (10 y) No legacy effect | Different comparison in OFU: treatment-naïve vs. not naïve |
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Pothen, L.; Balligand, J.-L. Legacy in Cardiovascular Risk Factors Control: From Theory to Future Therapeutic Strategies? Antioxidants 2021, 10, 1849. https://doi.org/10.3390/antiox10111849
Pothen L, Balligand J-L. Legacy in Cardiovascular Risk Factors Control: From Theory to Future Therapeutic Strategies? Antioxidants. 2021; 10(11):1849. https://doi.org/10.3390/antiox10111849
Chicago/Turabian StylePothen, Lucie, and Jean-Luc Balligand. 2021. "Legacy in Cardiovascular Risk Factors Control: From Theory to Future Therapeutic Strategies?" Antioxidants 10, no. 11: 1849. https://doi.org/10.3390/antiox10111849
APA StylePothen, L., & Balligand, J. -L. (2021). Legacy in Cardiovascular Risk Factors Control: From Theory to Future Therapeutic Strategies? Antioxidants, 10(11), 1849. https://doi.org/10.3390/antiox10111849